Head and neck squamous cell cancer (HNSCC) is a leading cause of death and disfigurement. A major limitation to improving treatment outcomes and survival has been a lack of understanding regarding cellular mechanisms involved in carcinogenic growth of relevant cells and thus a lack of mechanistically targeted therapies. Recent studies indicate that human papillomavirus (HPV) plays a major role in the development of HNSCC. Up to 60% of tonsillar SCC may be attributable to HPV infections. Compelling evidence indicates that HPV-related HNSCC is more common in patients with HIV, and recent studies suggest that antiretroviral therapies have no effect on reducing HPV-associated lesions. Despite the development of a prophylactic vaccine for HPV, there is no evidence that the vaccine would be effective at preventing HNSCC, particularly cancers associated with HIV infection. We have developed a unique in vitro and in vivo model system using human and mouse tonsillar epithelial cells to study progression to invasive malignancy. Our long-term goal is to understand key events of HPV-related tonsil epithelial cell transformation, and to use this information to develop molecular therapies that may be applicable to both HPV-positive and -negative HNSCC. We propose that HPV-mediated transformation and progression to malignancy depends on a novel HPV16 E6 oncoprotein function that is associated with its PDZ binding motif. We hypothesize that E6 mediated degradation of a PDZ containing tyrosine phosphatase, PTP-BL/FAP-1, is critical for an epithelial to mesenchymal transition (EMT) and anchorage independent growth (AIG), both key changes associated with the development of carcinomas. In these studies we will determine 1) what factors are required for malignant transformation of mouse and human tonsillar epithelial cells and whether loss of PTP-BL/FAP-1 is critical for this process, 2) how HPV E6 specifically degrades PTP-BL/FAP-1, and 3) the molecular mechanisms by which loss of PTP-BL/FAP-1 causes EMT and malignant progression. These studies will provide critical data for designing strategies to overcome EG-mediated transformation and may provide insight into treating non-HPV associated cancers. The knowledge gained from this work should make it possible to refine diagnostic and therapeutic methods for the treatment of HNSCC, an area of considerable unmet medical need, particularly in patients who suffer from complications associated with AIDS.